1. Saeedi, P, Petersohn, I, Salpea, P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract 2019; 157: 107843.
Google Scholar | Crossref2. International Diabetes Federation . IDF diabetes atlas, https://www.diabetesatlas.org/en/ (2019, accessed 22 February 2021).
Google Scholar3. Chatterjee, S, Khunti, K, Davies, MJ. Type 2 diabetes. Lancet 2017; 389: 2239–2251.
Google Scholar | Crossref | Medline4. Zimmet, PZ . Diabetes and its drivers: the largest epidemic in human history. Clin Diabetes Endocrinol 2017; 3: 1.
Google Scholar | Crossref | Medline5. Inzucchi, SE, Bergenstal, RM, Buse, JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015; 38: 140–149.
Google Scholar | Crossref | Medline6. Handelsman, Y, Bloomgarden, ZT, Grunberger, G, et al. American Association of Clinical Endocrinologists and American College of Endocrinology – clinical practice guidelines for developing a diabetes mellitus comprehensive care plan – 2015. Endocr Pract 2015; 21(Suppl. 1): 1–87.
Google Scholar | Crossref | Medline7. Ohkubo, Y, Kishikawa, H, Araki, E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995; 28: 103–117.
Google Scholar | Crossref | Medline8. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).UK Prospective Diabetes Study (UKPDS) Group . Lancet 1998; 352: 837–853.
Google Scholar | Crossref9. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) . UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 854–865.
Google Scholar | Crossref | Medline10. Khunti, K, Wolden, ML, Thorsted, BL, et al. Clinical inertia in people with type 2 diabetes: a retrospective cohort study of more than 80,000 people. Diabetes Care 2013; 36: 3411–3417.
Google Scholar | Crossref | Medline11. Bailey, CJ, Tahrani, AA, Barnett, AH. Future glucose-lowering drugs for type 2 diabetes. Lancet Diabetes Endocrinol 2016; 4: 350–359.
Google Scholar | Crossref | Medline12. Stumvoll, M, Goldstein, BJ, van Haeften, TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet 2005; 365: 1333–1346.
Google Scholar | Crossref | Medline13. Poitout, V, Robertson, RP. Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr Rev 2008; 29: 351–366.
Google Scholar | Crossref | Medline14. Butler, AE, Janson, J, Bonner-Weir, S, et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003; 52: 102–110.
Google Scholar | Crossref | Medline15. Prentki, M, Nolan, CJ. Islet beta cell failure in type 2 diabetes. J Clin Invest 2006; 116: 1802–1812.
Google Scholar | Crossref | Medline16. Defronzo, RA . Banting lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009; 58: 773–795.
Google Scholar | Crossref | Medline17. DeFronzo, RA . Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988; 37: 667–687.
Google Scholar | Crossref | Medline18. DeFronzo, RA . Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia 2010; 53: 1270–1287.
Google Scholar | Crossref | Medline19. Samuel, VT, Shulman, GI. Mechanisms for insulin resistance: common threads and missing links. Cell 2012; 148: 852–871.
Google Scholar | Crossref | Medline20. Magnusson, I, Rothman, DL, Katz, LD, et al. Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. J Clin Invest 1992; 90: 1323–1327.
Google Scholar | Crossref | Medline21. Matsuda, M, Defronzo, RA, Glass, L, et al. Glucagon dose-response curve for hepatic glucose production and glucose disposal in type 2 diabetic patients and normal individuals. Metabolism 2002; 51: 1111–1119.
Google Scholar | Crossref | Medline22. Baron, AD, Schaeffer, L, Shragg, P, et al. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes 1987; 36: 274–283.
Google Scholar | Crossref | Medline23. Gerich, JE, Meyer, C, Woerle, HJ, et al. Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care 2001; 24: 382–391.
Google Scholar | Crossref | Medline24. Baron, AD . Hemodynamic actions of insulin. Am J Physiol 1994; 267: E187–E202.
Google Scholar | Crossref | Medline25. DeFronzo, RA, Ferrannini, E, Hendler, R, et al. Influence of hyperinsulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange. Proc Natl Acad Sci USA 1978; 75: 5173–5177.
Google Scholar | Crossref | Medline26. Ferrannini, E, Simonson, DC, Katz, LD, et al. The disposal of an oral glucose load in patients with non-insulin-dependent diabetes. Metabolism 1988; 37: 79–85.
Google Scholar | Crossref | Medline27. Sharma, D, Verma, S, Vaidya, S, et al. Recent updates on GLP-1 agonists: current advancements & challenges. Biomed Pharmacother 2018; 108: 952–962.
Google Scholar | Crossref | Medline28. Meloni, A, DeYoung, M, Lowe, C, et al. GLP-1 receptor activated insulin secretion from pancreatic β-cells: mechanism and glucose dependence. Diabetes Obes Metab 2013; 15: 15–27.
Google Scholar | Crossref | Medline29. Rosenstock, J, Aronson, R, Grunberger, G, et al. Benefits of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide, versus insulin glargine and lixisenatide monocomponents in type 2 diabetes inadequately controlled on oral agents: the LixiLan-O randomized trial. Diabetes Care 2016; 39: 2026–2035.
Google Scholar | Crossref | Medline30. Hinnen, D, Strong, J. iGlarLixi : a new once-daily fixed-ratio combination of basal insulin glargine and lixisenatide for the management of type 2 diabetes. Diabetes Spectr 2018; 31: 145–154.
Google Scholar | Crossref | Medline31. Aroda, VR, Rosenstock, J, Wysham, C, et al. Efficacy and safety of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide in type 2 diabetes inadequately controlled on basal insulin and metformin: the LixiLan-L randomized trial. Diabetes Care 2016; 39: 1972–1980.
Google Scholar | Crossref | Medline32. Gough, SC, Bode, B, Woo, V, et al. Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes. Lancet Diabetes Endocrinol 2014; 2: 885–893.
Google Scholar | Medline33. Buse, JB, Vilsboll, T, Thurman, J, et al. Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care 2014; 37: 2926–2933.
Google Scholar | Crossref | Medline34. Perreault, L, Rodbard, H, Valentine, V, et al. Optimizing fixed-ratio combination therapy in type 2 diabetes. Adv Ther 2019; 36: 265–277.
Google Scholar | Crossref | Medline35. Gough, SC, Bode, BW, Woo, VC, et al. One-year efficacy and safety of a fixed combination of insulin degludec and liraglutide in patients with type 2 diabetes: results of a 26-week extension to a 26-week main trial. Diabetes Obes Metab 2015; 17: 965–973.
Google Scholar | Crossref | Medline36. Campbell, JE, Drucker, DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 2013; 17: 819–837.
Google Scholar | Crossref | Medline37. Nauck, MA, Meier, JJ. Incretin hormones: their role in health and disease. Diabetes Obes Metab 2018; 20(Suppl. 1): 5–21.
Google Scholar | Crossref | Medline38. Nauck, MA, Meier, JJ. GIP and GLP-1: stepsiblings rather than monozygotic twins within the incretin family. Diabetes 2019; 68: 897–900.
Google Scholar | Crossref | Medline39. Gasbjerg, LS, Bergmann, NC, Stensen, S, et al. Evaluation of the incretin effect in humans using GIP and GLP-1 receptor antagonists. Peptides 2020; 125: 170183.
Google Scholar | Crossref | Medline40. Eli Lilly and Company . Tirzepatide achieved superior A1C and body weight reductions across all three doses compared to injectable semaglutide in adults with type 2 diabetes, https://investor.lilly.com/news-releases/news-release-details/tirzepatide-achieved-superior-a1c-and-body-weight-reductions (2021, accessed 10 March 2021).
Google Scholar41. Frias, JP, Nauck, MA, Van, J, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet 2018; 392: 2180–2193.
Google Scholar | Crossref | Medline42. Coskun, T, Sloop, KW, Loghin, C, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab 2018; 18: 3–14.
Google Scholar | Crossref | Medline43. Willard, FS, Douros, JD, Gabe, MB, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight 2020; 5: e140532.
Google Scholar | Crossref | Medline44. Frías, JP . Tirzepatide: a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) dual agonist in development for the treatment of type 2 diabetes. Expert Rev Endocrinol Metab 2020; 15: 379–394.
Google Scholar | Crossref | Medline45. Bastin, M, Andreelli, F. Dual GIP-GLP1-receptor agonists in the treatment of type 2 diabetes: a short review on emerging data and therapeutic potential. Diabetes Metab Syndr Obes 2019; 12: 1973–1985.
Google Scholar | Crossref | Medline46. Gallo, LA, Wright, EM, Vallon, V. Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. Diab Vasc Dis Res 2015; 12: 78–89.
Google Scholar | SAGE Journals47. Kanai, Y, Lee, WS, You, G, et al. The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest 1994; 93: 397–404.
Google Scholar | Crossref | Medline48. Gorboulev, V, Schürmann, A, Vallon, V, et al. Na(+)-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 2012; 61: 187–196.
Google Scholar | Crossref | Medline49. Rieg, T, Masuda, T, Gerasimova, M, et al. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am J Physiol Renal Physiol 2014; 306: F188–F193.
Google Scholar | Crossref | Medline50. Wright, EM, Loo, DD, Hirayama, BA. Biology of human sodium glucose transporters. Physiol Rev 2011; 91: 733–794.
Google Scholar | Crossref | Medline